Implantable polymer for bone and vascular lesions

ABSTRACT

A solidifying implant composition of a polymer mixed with a bioabsorbable solvent. A method of treating a patient, by implanting the solidifying implant composition into bone, and solidifying the implant composition. A method of improving bone structure in patients by applying the solidifying implant composition to bone, shoring up bone structure, and improving load bearing capacity and aiding healing of microfractures. A method of fixing an implant, by applying the solidifying implant composition to an implant, and shoring up the implant. A method of devascularizing and treating a tumor or vascular lesion. A method of treating a vascular disease. A method of treating aneurysms/pseudoaneurysms.

BACKGROUND OF THE INVENTION

1. Technical Field

The present invention relates to compositions and methods of treatingbone fractures. In particular, the present invention relates tocompositions made of polymers and ceramics for treating bone fractures,lesions, voids, and temporary or permanent fixation of implants.Additionally, the present invention relates to compositions made ofpolymers for treating vascular lesions and visceral fistulas.

2. Background Art

Progressive loss of bone density or thinning of bone tissue arecharacteristics of osteoporosis, the most common type of bone diseaseaffecting 10 million Americans. Although regular exercise with dailyintake of vitamin and mineral supplements can help alleviate thesymptoms of osteoporosis, they do not provide wholesome treatment tothose experiencing osteoporosis-induced fractures. The early stages ofthis disease yield little to no symptoms; however, as the diseaseprogresses to late stage, patients begin to experience various symptoms,including: low back pain, bone pain, fractures with little to no trauma,and kyphosis. Bone mineral testing quantitatively measures bone densitywithin a patient. These tests can accurately predict the risk for bonefractures in the future. From these tests, high-risk patients can beprescribed a variety of different medications, including, but notlimited to: bisphosphonates, calcitonin, hormone replacement therapy,parathyroid hormone, raloxifene, or advised regular exercise with abalanced, nutritional diet.

Although these medications and routine changes can help preventfractures, it cannot reverse pre-collapsed vertebrae, or regeneratelarge quantity bone defects created by trauma, infection, skeletalabnormalities or tumor resection. The aforementioned problems go beyondnormal potential for self-healing within the bones; therefore, clinicaltreatment becomes necessary.

Clinical treatment for collapsed vertebrae includes vertebroplasty orkyphoplasty. Within vertebroplasty, physicians inject a cement mixtureinto the fractured segment of the vertebrae, whereas in kyphoplasty, aballoon is inserted before cement injection to create a cavity or space.Once the balloon is removed, the cement can be injected into the cavity.Although these clinical procedures allow the patient to regainfunctional abilities without pain, they carry various risks with them aswell, including: risk of infection, risk of orthopedic cement leakageout of vertebral body that can cause pulmonary edema if cement migratedto the lungs, secondary fracture of the adjacent vertebra if cementleaks into the disk space, and neurological symptoms if cement leaksonto spinal nerves.

Clinical treatment for trauma-induced, infection-induced,osteoporosis-induced or tumor-induced fractures includes insertion ofone or more screws across the fracture point, insertion of a steel plateheld by screws across the fracture point, insertion of a long metal roddriven down the shaft of the bone, or, in severe cases, bone graftingand joint replacement will be considered. The most common problem thatarises from osteoporosis-induced fractures is failure of fixation of theaforementioned screws, metal plate, or rod due to the decreased bonedensity in the osteoporotic patient.

Surgeons attempt to decrease failure of fixation by reinforcement of thesurgical prosthesis with bone cement. This cement fills in the voidbetween the prosthesis and the bone.

Currently, bone cements are supplied as two-component materials. Onecomponent consists of a powder; the second component consists of aliquid. The powder component is made from, but not limited to,poly(methyl-methacrylate) (PMMA), PMMA with various salt additives,calcium phosphate, and bioactive glass substitutes. The liquid componentis made from, but not limited to, a stabilizer, an inhibitor, and a MMAmonomer. These two components are mixed together in a certain ratiounder vacuum-sealed conditions. Once the mixture is homogeneous, thebone cement is injected into a void and allowed to harden.

The optimal bone cement has properties that mimic natural human bonethat include, but are not limited to, cement pore size between 50microns to 150 microns, high pore connectivity, osteoconductiveproperties, and comparable Young's modulus to that of natural bone.

The disadvantage of current PMMA based bone cements is their physicalproperties, lack of osteoconductivity, and resorption. This prevents thePMMA from being properly integrated into the bone, and instead, the PMMAis encapsulated by a connective tissue layer. Furthermore, PMMA basedbone cements require relatively high temperatures of 82.5 degrees C.while setting. Surrounding tissues exposed to such high heat undergothermal tissue necrosis. Additionally, PMMA based bone cements are knownto have a Young's modulus greater that of natural bone, therefore,natural stresses experienced by the bone during motion induced by thepatient are loaded into the cement, rather than the bone. When thenatural bone stops receiving mechanical signals from daily movement bythe patient, bone remodeling comes to a standstill and worsensosteoporotic weakening of the bone. This can lead to a revision surgery.The difficulty and length of the revision surgery is increase by thedifficulty in removing current bone cements.

The disadvantage of PMMA infused with various salt additives has similardisadvantages as aforementioned for sole PMMA based bone cements.

The disadvantages of calcium phosphate based bone substitute include,but are not limited to, large pore size, and low Young's modulus. Poresize of 230 microns was found in various calcium phosphate based bonesubstitute. Although macroporosity (pores>100 microns) is important forosteoconductivity and revascularization, pore sizes of 230 microns havefewer interconnected pores, and therefore, have suboptimalosteoconductivity. Furthermore, large pore sizes within calciumphosphate based bone substitute yield poor compressive strength, andtherefore, low Young's modulus. This poor compressive strength will notadequately stabilize bone or implants in loadbearing applications, andtherefore would lead to failure because these bone substitutes are notload-bearing prior to bone regeneration.

The disadvantage of bioactive glass substitutes includes, but is notlimited to, poor resorption in natural bone. Although bioactive glasssubstitutes possess superior mechanical strength, varying pore sizesbetween 50-150 microns, and high connectivity between pores, thesubstitute has a poor resorption rate, and therefore, the natural bonehas hindered growth.

There are several challenges with current liquid embolic technologies.Frequently embolization of vascular lesions is required to treat, reduceblood flow prior to or following incomplete surgical treatment ofvarious vascular diseases. Currently, there are not effective treatmentsavailable or available treatments options are dangerous, painful, anddebilitating. The available methods for endovascular treatment ofvascular lesions are often ineffective and require numerousre-treatments. The buildup of radiopaque material from multipleinjections, large injections, or subsequent embolization proceduresmakes imaging and safely navigating the vascular lesion more difficult,takes longer, and limits the imaging options. Difficulty visualizing thevascular lesion leads to increased procedural times, radiation dose tothe patient and surgical staff, and treatment cost. Patients frequentlyget radiation burns and lose hair from the prolonged exposure.

Current devices approved for treatment and/or occlusion of venousvarices, vascular tumors, and traumatic vessel injury are awkward, lackcontrol, and are often incomplete or require multiple treatments.Endovascular treatment of brain arteriovenous malformations often doesnot completely and durably occlude the lesion. More invasive anddangerous treatment with open neurovascular surgery or single, high dosestereotactic radiation (which may be incompletely effective, or requirea significant therapeutic interval during which the patient is notprotected from cerebral hemorrhage) can be required for these patientwho cannot be completely and durably treated by minimally invasivemethodologies. Endovascular devices and surgical repair of aneurysms maynot completely and durably occlude certain lesions and may requireretreatment.

The radiopaque materials used in embolic agents can spark and ignitedthe embolic material in the patient during surgical resection. Surgeonsfrequently use mono cautery during open surgical procedures. The monocautery initially causes the radiopaque particles to spark followed bythe embolic material catching on fire. The fire can last for severalseconds after the surgeon stops using the cauterization.

The solvent volume used in current liquid embolic agents is not safe orcompatible for many procedures. The current product, Onyx, uses DMSO atconcentration from 94% to 80% by molecular weight. DMSO affects nervesby inhibiting cholinesterase. The effect of DMSO on nerves is typicallyseen after a vessel is occluded; when the DMSO concentration builds upin the surrounding tissue. DMSO can also cause an acute tissue response.This was demonstrated when Onyx did not meet the FDA requirement of aUSP 7-day muscle implant evaluation because implantation resulted in anacute tissue response. DMSO can cause spontaneous skeletal musclefasciculations. Making visualization difficult for the surgeon andcausing pain for the patient. These procedures are converted to anintubated procedure increasing the risk and cost of the treatment. DMSOability to lower the vagal threshold could be a cause of the bradycardiaseen when using Onyx near the valgus nerve.

Open surgical treatment is dangerous, debilitating and more costly.Currently, no optimal and safe device exists for endovascular treatmentfor many arteriovenous malformations, arteriovenous fistulae, orvisceral and/or viscerocutaneous fistulae.

Therefore, there remains a need for a method for developing a bonecement, scaffold, which caters to the aforementioned problems withcurrent bone cement technologies and aims to incorporate: a broad rangeof drug-eluting properties including using nano-particle for delivery,infusion of radio-opaque components, biodegradability of the bonecement, improved load bearing functionality, and elimination of thetwo-component dry and wet based system for mixing bone cements.Furthermore, there remains a need for a treatment for vascular diseasesthat is less invasive, allows for more precise control, improvedvisibility, and more efficacious treatment.

SUMMARY OF THE INVENTION

The present invention provides for a solidifying implant composition fortreating fractures, lesions, voids, and temporary or permanent fixationof implants including a polymer mixed with a biocompatible solvent.

The present invention also provides for a method of treating a patientby implanting the solidifying implant composition of a polymer mixedwith a biocompatible solvent into bone, and solidifying the implantcomposition.

The present invention provides for a method of improving bone structurein patients by applying the solidifying implant composition of a polymermixed with a biocompatible solvent to bone, shoring up bone structure,and improving load bearing capacity and aiding healing ofmicrofractures.

The present invention provides for a method of fixing an implant, byapplying the solidifying implant composition of a polymeric materialmixed with a biocompatible solvent to an implant, and shoring up theimplant.

The present invention provides for a method of devascularizing a tumoror vascular lesion by applying the solidifying implant composition of apolymer mixed with a bioabsorbable solvent to a tumor or vascularlesion.

The present invention also provides for a method of treating a vasculardisease by applying the solidifying implant composition of a polymermixed with a bioabsorbable solvent to vascular site in need oftreatment.

The present invention also provides for a method of treatinganeurysms/pseudoaneurysms by applying the solidifying implantcomposition of a polymer mixed with a bioabsorbable solvent to ananeurysm/pseudoaneurysm.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a solidifying implant composition fortreating fractures, other bone conditions, and vascular diseases,generally including polymeric material mixed with a polar biocompatiblesolvent.

Before insertion into the body, the composition is in the form of aninjectable fluid or a malleable paste. The composition solidifies whenplaced in contact with living tissue or liquid by absorption anddiffusion of the solvent into the surrounding tissue or liquid, suchthat solidification is preferably temperature independent. However,solidification can also be temperature dependent.

The polymeric material (polymers and copolymers) used in the compositioncan include, but is not limited to, acrylics includingpolymethylmethacrylate (PMMA), polyethylene UHMW(ultra-high-molecular-weight) and PEX (cross-linked polyethylene)(implants, artificial joints), polypropylene, polyesters, polybutyleneterephtalate (PBT), VECTRA® Liquid Crystal Polymer (LCP) (Ticona),polyetherekketone (PEEK-), polystyrene mono- and copolymer,polybutadiene mono- and copolymer, polyvinyl alcohol mono- andcopolymer, polyamides (nylon), polyglycolic acid (PGA), polylactic acid(PLA), polyglycolic-lactic acid (PGLA), polyurethanes, calciumphosphates, calcium sulphates, hydroxyapatite, silicates, bioactiveglasses, diacetonylacrylamide, polylactides, polydioxannones,polycarbonates, polyalkene oxylates, polyanhydrides, polyamides,polyesteramides, polyurethanes, polyacetals, polyketals,polyorthocarbonates, polyphosphazenes, polyhydroxyvalerates,polyalkylene succinates, poly(malic acid), poly(amino acids), Chitin,Chitosan, polyorthoesters, polyhydroxybutyrates, polyethylene glycol,porous silicon, collagen, hyaluronic acid, and copolymers, terpolymers,and combinations of the above polymers. Multiple polymeric materials canbe used in the composition in combination with a single solvent ormultiple solvents as futher described in the Examples below.

The solvent used in the composition is any solvent that can dissolve thepolymeric material and water, including water itself, is biocompatibleand preferably bioabsorbable (i.e. able to be absorbed by the body), andcan include, but is not limited to, dimethyl sulfoxide (DMSO), acetone,2-butanol, ethanol, ethyl acetate, methyl acetate, dimethylformamide,caprolactam, oleic acid, 1 propanol, 2-propanol, propyl acetate,propylene glycol, glycerol, or any solvent analogous/homologous todimethyl sulfoxide, and combinations thereof. The solvent can be inexcess to dissolve polymers and other materials and yield variableviscosities that enhance ability to sculpt product to unique clinicalsituations that are present in each individual patient. When mixed, thesolvent and polymer can form a hydrogel, aerosol gel, or other gel. Thesolvent can also optionally additionally include other solvents that arenot bioabsorbable.

The composition can further include radiopaque or radioactive isotopematerials and particles such as, but not limited to, Tantalum, Platinum,Barium, Titanium, Silver, Gold, Palladium, Iridium, Osmium, Copper,Niobium, Molybdenum, Strontium and Gallium and/or alloys such asNickel-Titanium, Nickel-Manganese-Gallium, Platinum-Iridium andPlatinum-Osmium, and combinations thereof to enhance visualization ofthe injected material (act as contrast agents) and improve thestructural integrity and performance of the implant. Visibility of thesematerials can degrade over time.

The composition can also further include a catalyst such as Platinum,Palladium, peroxide, metal salts, Zinc, enzymes, redox couples, orcombinations thereof to increase the speed of polymerization.

The composition can further include suspended particles of micro- ornano-scale biologically active material for localized targeted ornon-targeted delivery. The biologically active material can betherapeutic agents or combinations of therapeutic agents such asproteins, drugs, or other agents. For example, antibiotics such asVancomycin, Amikacin or Tetracycline and/or metals such as Silver orCopper can be included to prevent infection at an area to which thecomposition is applied. The biologically active material can be releasedspecifically at the site of implantation of the composition. Thus, thecomposition can be used for site-specific delivery of therapeutic agentsto stimulate or aid in bone healing such as bisphosphonates andhydroxyapatite. Pain relief therapeutics can be included such asparacetamol (acetaminophen), non-steroidal anti-inflammatory drugs(NSAIDs), and COX-inhibitors. Cancer treatments can also be includedsuch as chemotherapeutics agents such as Methotrexate and inhibitors ofcancer growth such as Gallium. These biologically active materials canbe delivered buffered within the implant solution or within micro- ornanoparticles suspended within the implant.

The composition can further include biodegradable polymers, such aspolyglycolic acid (PGA), polylactic acid (PLA), polyglycolic-lactic acid(PGLA), polycaprolactone (PCL), ε-poly-L-lysine (EPA),glycosaminoglycans (GAGs), polyalcohols, heparinoids, and combinationsthereof that can initially prevent blood from clotting, providecohesiveness and improve control during injection, create avenues forenhanced in-growth of supporting cells and improve healing bystimulating tissue ingrowth as they are degraded over time, andproviding a mechanism for delivering targeted therapeutics via chemicalattachment to side groups.

The composition can further include polymeric, ceramic or metal fibers,filaments, coils, or particles, or combinations thereof, such asmicroparticles or nanofibers, which can increase structural andmechanical integrity, flexibility, durability, and cohesiveness of theresulting implant. Examples of ceramics are hydroxyapatite, calciumsilicate, tri-calcium phosphate, biphasic calcium phosphate, or kaolinproviding scaffolding for cellular in-growth and enhancingosseointegration.

The composition can also further include a liquid contrast agent such asEthiodol, and/or a powder such as Tantalum and/or Barium Sulfate, and/oran alloy such as Nickel-Titanium to enhance visualization of thematerial during implantation.

The implant composition can be prepared by methods known in the art bymixing the polymeric material with the solvent and optionally any of theother compounds as described above. Many other materials can be added toprovide the final composition with additional properties. Metals such asTantalum and/or contrast agents such as Ethiodol can be added to thepolymeric material and mixed immediately prior to injection, such aswith Trufill n-Butyl Cyanoacrylate. Additionally, metals such asTantalum can be added to the polymeric material during manufacture andagitated vigorously to suspend the metal immediately prior to injection,such as with Onyx Liquid Embolic System for brain arteriovenousmalformation and Onyx HD for brain aneurysm treatment. Additionally,various components such as polymeric material monomer, a contrast agentsuch as powdered Barium Sulfate, and antibiotics such as gentamicin canbe added together and mixed injected. Furthermore, a first polymericmaterial (and optionally additional different polymeric material) can bemixed with a first solvent, and then a second, different polymericmaterial (and optionally additional different polymeric material) can beadded with or without additional solvents as described in the Examplesbelow.

The composition of the present device can be delivered inself-contained, single use, sterilized packaging that may need to beagitated to suspend metal contrast material prior to delivery.

The composition of the present invention can create an implant thatprovides support, stability, load bearing and fixation for fractureswhile at the same time dampening stress to prevent fracture of adjacentboney structures and allow controlled movement of the fractured bonethat promotes faster and stronger healing of the fractured bone. Oncesolidified, the composition acts as a scaffold for ingrowth andregeneration of bone tissue. The implant is capable of mimicking bone,vascular, and other tissue. The implant can be permanent, or can bebiodegradable, or bioabsorbable. The composition of the presentinvention thus overcomes many of the drawbacks of compositions of theprior art.

The solidified composition possesses mechanical properties, which areimproved upon the prior art for the applications of bone stabilization.The composition can have a structure such that is possesses compressivestrength within the range of 10-500 MPa, it possesses elastic modulusbetween 0.1-100 GPa, and it possesses yield strength within 0.5-10 MPa.These properties improve strength, while dampening—but not entirelyremoving—stress to prevent weakening (stress shielding) and fracture ofadjacent boney structures and allow controlled movement of the fracturedbone that promotes faster and stronger healing of the fractured bone.

The consistency of the composition can be similar that of the naturaltissue to absorb and decrease transfer of energy in order to promotenormal function in the adjacent tissue. The consistency also allowssurgical handling when the device is used as an adjunct to surgery.

The composition can have a structure that facilitates pore formationwithin and upon the surface of the implant within a range of 1-1000 μμm(target mean pore size 50-150 μm) and <10 μm, respectively, in order tofacilitate osteoblast ingrowth and protein absorption.

The solidified composition can possess degradation properties thatfacilitate the ingrowth of new tissue formation or release oftherapeutics. These properties, such as the rate of degradation, can becontrolled by material selection and pore sizes, connectivity, or volumeto match degradation with bone growth or desires therapeutic release.

The composition is suitable for uses such as, but not limited to,vertebroplasty, kyphoplasty, void filling, bone stabilization, orstabilization of nonresorbable materials in contact with bone (fixationscrews or implants) in mammals.

The composition of the present invention improves upon substances usedin the prior art for other purposes for new applications discussedherein. A combination of a polymer and a solvent has been used in thepast for other applications such as treating cerebrovascular diseases,specifically brain arteriovenous malformations and aneurysms, but thematerials that are available are not cohesive and therefore are noteffective for long-term treatment of fractures because they fall apartunder stress. Hydroxyapatite has been used in similar applications, butlacks structural integrity to resist compression during load bearing.The composition of the present invention integrates the beneficialproperties of disparate substances to provide a whole that is greaterthan the sum of the parts: each component supports the other componentsand yields a composite that combines the strength of each material whileeliminating the inherent individual weaknesses. Thus, the composition ofthe present invention is a synergistic composition.

The composition of the present invention also provides the followingadditional advantages. The opacity of the material of the compositioncan diminish over time. When made to be radiopaque, the material can bedelivered in particles, spheres, or liquids that degrade over timedecreasing the radio density. The radiopaque material can be insuspension. This can include using nanoparticles to aid in thedissipation of the radiopaque material of a PEG or other polymericmaterial. The radiopaque material can lose its radiopacity over time.The composition of the present invention is a better liquid embolic thanthe prior art. Also, the combined the benefits of using a solvent todeliver a polymeric material with a thermal responsive polymericmaterial or hydrogel decreases the volume or change the solvent needs,increases the control of the material and cohesiveness of the material,improving the effectiveness and safety of endovascular embolization.

The present invention provides for a method of treating patients,including all types of mammals, by implanting the composition of thepolymeric material mixed with a bioabsorbable solvent into bone asdescribed above, and solidifying the implant composition. Theimplantation or application of the composition can occur by methods thatare routine in surgical procedures for orthopaedics, such asvertebroplasty or fixing fractures. The composition can be administeredin various ways, but preferably the implantation is performed byinjecting the composition to the site of need. Hence, viscosity,absorption of solvent, etc. are critical parameters that can be adjusteddepending on the use and environment. The composition can be premixedprior to injection, can be mixed in the injector device, can be mixedduring injection, mixed in situ or a combination of these methods duringthe injection process. When mixed in situ, the composition and othercomponents are caused to be mixed right at the site of application inthe body. The composition can be injected with a needle with gaugesincluding, but not limited to, down to a 22 gauge.

In the solidifying step, as described above, the implant composition canbe solidified upon contact with surrounding tissue or liquid byabsorbing and diffusing the solvent into the surrounding tissue orliquid. After the solvent has absorbed and diffused away, pores areformed in its place within and on the surface of the implantcomposition. Additionally the composition can be solidified using across linker, curing agent, enzyme, a thermosensitive polymer, orcombination of the above or similar curing methods. The implant canremain in the body permanently, or it can be biodegradable orbioabsorbable.

This method can be used to treat a variety of medical conditions inprocedures, such as, but not limited to, vertebroplasty, kyphoplasty,void filling, bone stabilization, or stabilization of nonresorbablematerials in contact with bone (fixation screws or implants) in mammals.

Currently, there is no available product or method that addresses alltypes of bone fractures. This method can be used to treat bone fracturesthat can include, but are not limited to, bone fractures, osteoporoticbone fractures, compression fractures, stress fractures, pathologicalfractures, non-union fractures, complex fractures, displaced fractures,and poor-healing fractures.

The composition can also further absorb and distribute stress to preventfatigue and fracture of adjacent bone. These characteristics improvedurability of the implant composition.

The composition can also be used in a method of improving bone structurein patients, by applying the composition to bone, shoring up bonestructure and improving load bearing capacity and aiding healing ofmicrofractures. The composition can also be temporarily stabilized afterthe bone structure has been shored up. By this temporary stabilization,subsequent procedures can be made less difficult. The composition can beapplied either by injecting the composition into or coating thecomposition on the bone or an implant. Preferably, this method is usedto treat patients that are suffering from severe osteoporosis,metastases, or other bone lesions at risk of catastrophic failure. Thesolidified composition can remain in the body permanently, or it can bebiodegradable or bioabsorbable.

The composition can further be used in a method of fixing an implant, byapplying the composition to an implant, and shoring up the implant. Thismethod can be useful for stabilizing implants in the body. Thesolidified composition can remain in the body permanently, or it can bebiodegradable or bioabsorbable.

The composition of the present invention can further be used in a methodof devascularizing a tumor or vascular lesion, by applying thecomposition including a polymeric material mixed with a bioabsorbablesolvent to a tumor or vascular lesion. The tumor or vascular lesion canalso further be treated with additional therapeutics, such as, but notlimited to, chemotherapy, radiotherapy, or other cancer therapeutics.

The composition can further be used in vascular applications. Thecomposition can also be used to address vascular diseases that currentlyhave no effective or inadequate endovascular treatment options orimprove upon existing endovascular treatment options. The compositioncan be applied to any area of a vascular site in need of treatment. Thisuse can be applicable to endoleaks that occur following endovascularrepair of aortic aneurysms, aneurysms, spinal and body arteriovenousmalformations and fistulae, cerebral and spinal dural arteriovenousfistulae, traumatic vessel injury (traumatic vascular lesion), venousvarices, visceral and/or viscerocutaneous fistulae and vascular tumorsand improve treatment of cerebral arteriovenous malformations.

More specifically, the composition can be delivered into the space thatis filled by blood or other body fluids and track along those avenues tofind and fill the in-flow and out-flow of endoleak sacs, arteriovenousmalformations and fistulae and varices at various sites in the bodyincluding the brain and spinal cord and their lining tissues, otherorgans and muscles, and viscera, or abnormal connections between visceraand skin.

Therefore, the composition of the present invention can also be used ina method of treating aneurysms/pseudoaneurysms by applying thecomposition including a polymeric material mixed with a bioabsorbablesolvent to an aneurysm/pseudoaneurysm.

There are several advantages to using the composition of the presentinvention in vascular applications. The composition can provide lessinvasive treatment of these very difficult lesions. The composition canalso allow more precise control, improved visibility, time dependentradiopacity, and more efficacious treatment of these lesions.

The compounds of the present invention are administered and dosed inaccordance with good medical practice, taking into account the clinicalcondition of the individual patient, the site and method ofadministration, scheduling of administration, patient age, sex, bodyweight and other factors known to medical practitioners. Thepharmaceutically “effective amount” for purposes herein is thusdetermined by such considerations as are known in the art. The amountmust be effective to achieve improvement including but not limited toimproved survival rate or more rapid recovery, or improvement orelimination of symptoms and other indicators as are selected asappropriate measures by those skilled in the art.

In the method of the present invention, the compound of the presentinvention can be administered in various ways. Preferably, thecomposition is injected to the site of need. Hence, viscosity,absorption of solvent, etc. are critical parameters that can be adjusteddepending on the use and environment. In vascular applications, thecomposition can also be delivered endovascularly to occlude arteries,veins, intervening vascular spaces, and abnormal connections ordisruptions of blood vessels or viscera, or tumors of the body, spine orbrain and surrounding structures.

The invention is further described in detail by reference to thefollowing experimental examples. These examples are provided for thepurpose of illustration only, and are not intended to be limiting unlessotherwise specified. Thus, the invention should in no way be construedas being limited to the following examples, but rather, should beconstrued to encompass any and all variations which become evident as aresult of the teaching provided herein.

EXAMPLE 1

This invention is defined by its ability to control several importantfunctional parameters of an injectable scaffold delivered via a solvent.This invention primarily features a polymer or co-polymer mix ofbiodegradable polymers and a crosslinking agent within a water misciblesolvent. In this example, a PLA-PGA co-polymer with a triolcross-linker, such as glycerol, in a DMSO solvent was used. Thiscombination is henceforth known as the “mix.” The nature of the deliveryof this scaffold is unique in that: the mix will retain its viscousliquid form prior to injection; upon injection and contact with bodilytissues and fluids the solvent will diffuse from the mix; and, as thesolvent diffuses the cross-linked, cohesive co-polymer will be leftbehind.

Alone and uncontrolled, this co-polymer scaffold is mechanicallylimited. Controlling the ratio of PLA-PGA in this mix is essential incontrolling not only the mechanical integrity, but also the degradationrate and porosity of the resulting scaffold.

PLA is comprised of polymeric chains of:

PGA is comprised of polymeric chains of:

The ratio of these two polymers together in a ring opening orcondensation reaction, in conjunction with controlling thestereochemistry of each individual polymer will play an important roleprimarily in controlling degradation rate. The COO ester groups on thesepolymers are essentially cleaved by esterases and water over time withinthe body, resulting in lactic acid and glycolic acid (which arenaturally occurring materials). The CH3 group on PGA makes it slower todegrade than PLA. Therefore, increasing the ratio of PLA over PGA in aco-polymer results in a material that lasts longer in the body.

The glycerol cross-linker acts to crosslink the PLA-PGA co-polymerchains giving the scaffold structural integrity and cohesiveness. Drawnfibers of PLA or PLA can be used to increase the structural integrity.Because these chains are cross-linked, when the DMSO solvent diffusesfrom the injection, pores are created in place of the solvent.

Furthermore, the percentage of DMSO solvent used in the mix can controlthe viscosity of the injection prior to solidification. A decrease insolvent percentage results in a more viscous and more controlled,cohesive injection.

Based on the chemistry of these two polymers the mechanical integritycan be controlled minimally. Larger side groups (CH3 in PLA) result inincreased mechanical integrity.

However, these polymers alone will not be mechanically strong(compressive strength) enough for application as a bone cement. Toimprove the mechanical strength and integrity of this mix, the use ofadditional materials and the bonds between these materials plays aprimary role.

In this example, a polyHEMA (hydroxyethylmethacrylate) hydrogel, whichhas OH groups interacting with water, can be used in conjunction withthe previously described mix. polyHEMA is described chemically below:

This hydrogel can be embedded with silicate or calcium phosphatesalts/fibers/filaments/coils that significantly increase the mechanicalstrength of the material, based on the length of these fibers and theconcentration of these fibers within the hydrogel. In conjunction withpolyHEMA, a material like a silicate or hydroxyapatite can improvecompressive strength due to the alignment of the molecular structure ofthe silicate itself. The nature of the polyHEMA can also act to retainthese materials within the scaffold.

The hydrogel can either be cured as a hydrogel prior to injection anddelivered into the body with the mix, or HEMA monomer can be added tothe mix and injected. As the HEMA+mix+a redox partner and peroxide areinjected and mixed together, the peroxide and a redox partner such as anenzyme, and HEMA undergoes a polymerization reaction resulting in acured, cohesive polyHEMA structure embedded with the PLA-PGA co-polymerblend with little heat released.

Furthermore, additional materials, such as the aforementioned fibers,therapeutics encapsulated in nanoparticles or PEG, therapeutics alone,or radiopaque metal salts can be embedded in the mix or pre-curedhydrogel prior to injection. As the DMSO solvent is diffused from thescaffold or the polyHEMA chains are cured, these additional materialsare captured within the scaffold. This provides a controlled release oftargeted or non-targeted therapeutics (by degradation of polymer,release from nanoparticles, or diffusion from hydrogel), radiopaquevisibility for ease of non-invasive injection, and increased mechanicalproperties due to fiber alignment.

EXAMPLE 2

The material includes a polymeric composition in a biocompatiblesolvent. Such a polymeric composition can contain two biodegradablepolymers combined as a copolymer, which are both soluble in the solvent.This can also contain a second composition including a monomer, whichcan be polymerized into a gel by a catalyst agent or a redox couple,which is mixed with the first composition. Additional insolubleparticles can be added in the solvent solution or the gel for mechanicalsupport of the resulting material.

Specifically, a first composition of PLA-co-PGA in a solvent, such asDMSO, can be combined with a second composition of a HEMA monomer. Whenthese are combined, a catalyst, such as an enzyme or a redoxcouple-ammonium persulphate (in composition 1) and ethylenediamenetetracetic acid (in composition 2), polymerize the HEMA into a gel.Insoluble particles, such as hydroxyapatite could then be mixed into thematerial either in the solvent or in the gel.

EXAMPLE 3

The material includes a polymeric composition in a biocompatiblesolvent. Such a polymeric composition can contain two biodegradablepolymers, which are both soluble in the solvent. This can also contain asecond composition comprising a monomer, which can be polymerized by acatalyst agent or a redox couple, which is mixed with the firstcomposition. Additional insoluble particles can be added in the solventsolution or the gel for mechanical support of the resulting material.

Specifically, a composition of PLA and PCL in a solvent, such as DMSO,can be combined with a second composition of an AA (acrylic acid)monomer. When these are combined, a catalyst, such as an enzyme or aredox couple-ammonium persulphate (in composition 1) and ethylenediamenetetracetic acid (in composition 2), polymerize the AA. Insolubleparticles, such as hydroxyapatite can then be mixed into the materialeither in the solvent or in the gel.

EXAMPLE 4

The material includes a polymeric composition in a biocompatiblesolvent. Such a polymeric composition can contain two biodegradablepolymers, which are both soluble in the solvent. This can also contain asecond composition of monomers, which can be polymerized into a gel by acatalyst agent or a redox couple, which is mixed with the firstcomposition. Additional insoluble particles can be added in the solventsolution or the gel for mechanical support of the resulting material.

Specifically, a composition of PLA and PCL in a solvent, such as DMSO,can be combined with a second composition comprising a HEMA and AAmonomers. When these are combined, a catalyst, such as an enzyme or aredox couple-ammonium persulphate (in composition 1) and ethylenediamenetetracetic acid (in composition 2), can polymerize the HEMA and AA intoa gel. Insoluble particles, such as hydroxyapatite can then be mixedinto the material either in the solvent or in the gel.

EXAMPLE 5

The material includes a polymeric composition in a biocompatiblesolvent. Such a polymeric composition can contain two biodegradablepolymers combined as a copolymer, which are both soluble in the solvent.This can also contain a second composition of a monomer, which can bepolymerized into a gel by a catalyst agent or a redox couple, which ismixed with the first composition. Additional insoluble particles can beadded in the solvent solution or the gel for mechanical support of theresulting material.

Specifically, a composition of PLA-co-PGA in a solvent, such as DMSO,can be combined with a second composition comprising an AA monomer. Whenthese are combined, a catalyst, such as an enzyme or a redoxcouple-ammonium persulphate (in composition 1) and ethylenediamenetetracetic acid (in composition 2), polymerize the AA into a gel.Insoluble particles, such as hydroxyapatite could then be mixed into thematerial either in the solvent or in the gel.

EXAMPLE 6

The material includes a polymeric composition in a biocompatiblesolvent. Such a polymeric composition can contain two biodegradablepolymers, which are both soluble in the solvent. This can also contain asecond composition of an already polymerized hydrogel material, which ismixed with the first composition. Additional insoluble particles can beadded in the solvent solution or the gel for mechanical support of theresulting material.

Specifically, a composition of PLA and PCL in a solvent, such as DMSO,can be combined with a second composition comprising a polyHEMA hydrogeland PEG. Insoluble particles, such as hydroxyapatite can then be mixedinto the material either in the solvent or in the gel.

EXAMPLE 7

The material includes a polymeric composition in a biocompatiblesolvent. Such a polymeric composition can contain two biodegradablepolymers, which are both soluble in the solvent. This can also contain asecond composition of an already polymerized hydrogel material, which ismixed with the first composition. Additional insoluble particles can beadded in the solvent solution or the gel for mechanical support of theresulting material.

Specifically, a composition of PLA and PCL in a solvent, such as DMSO,can be combined with a second composition of a polyAA hydrogel and PEG.Insoluble particles, such as hydroxyapatite can then be mixed into thematerial either in the solvent or in the gel.

With the above examples, in addition other combinations of the samematerials can be utilized to improve the properties of the bone cement.Other biodegradable and non-degradable polymer combinations can also beutilized.

Throughout this application, various publications, including UnitedStates patents, are referenced by author and year and patents by number.Full citations for the publications are listed below. The disclosures ofthese publications and patents in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this invention pertains.

The invention has been described in an illustrative manner, and it is tobe understood that the terminology, which has been used is intended tobe in the nature of words of description rather than of limitation.

Obviously, many modifications and variations of the present inventionare possible in light of the above teachings. It is, therefore, to beunderstood that within the scope of the appended claims, the inventioncan be practiced otherwise than as specifically described.

1. A solidifying implant composition, comprising a polymeric materialmixed with a biocompatible solvent.
 2. The solidifying implantcomposition of claim 1, wherein said composition is in a form chosenfrom the group consisting of an injectable fluid, a malleable paste, ahydrogel, and an aerosol gel.
 3. The solidifying implant composition ofclaim 1, wherein said polymeric material is chosen from the groupconsisting of polymethylmethacrylate (PMMA), polyethylene UHMW(ultra-high-molecular-weight), cross-linked polyethylene PEX,polypropylene, polyesters, polybutylene terephtalate (PBT),polyetherekketone (PEEK-Optima), polystyrene mono- and copolymer,polybutadiene mono- and copolymer, polyvinyl alcohol mono- andcopolymer, polyamides (nylon), polyglycolic acid (PGA), polylactic acid(PLA), polyglycolic-lactic acid (PGLA), polyurethanes, calciumphosphates, calcium sulphates, hydroxyapatite, silicates, bioactiveglasses, diacetonylacrylamide, polylactides, polydioxannones,polycarbonates, polyalkene oxylates, polyanhydrides, polyamides,polyesteramides, polyurethanes, polyacetals, polyketals,polyorthocarbonates, polyphosphazenes, polyhydroxyvalerates,polyalkylene succinates, poly(malic acid), poly(amino acids), Chitin,Chitosan, polyorthoesters, polyhydroxybutyrates, polyethylene glycol,porous silicon, collagen, hyaluronic acid, and copolymers, terpolymers,and combinations thereof.
 4. The solidifying implant composition ofclaim 1, wherein said solvent is chosen from the group consisting ofdimethyl sulfoxide (DMSO), acetone, 2-butanol, ethanol, ethyl acetate,methyl acetate, dimethylformamide, caprolactam, oleic acid, 1 propanol,2-propanol, propyl acetate, propylene glycol, glycerol, any solventanalogous or homologous to dimethyl sulfoxide, and combinations thereof.5. The solidifying implant composition of claim 1, wherein said solventis in excess.
 6. The solidifying implant composition of claim 1, furtherincluding a radiopaque metal particle chosen from the group consistingof Tantalum, Platinum, Barium, Titanium, Silver, Gold, Palladium,Iridium, Osmium, Copper, Niobium, Molybdenum, Strontium, Gallium,Nickel-Titanium, Nickel-Manganese-Gallium, Platinum-Iridium,Platinum-Osmium, and combinations thereof.
 7. The solidifying implantcomposition of claim 1, further including a catalyst chosen from thegroup consisting of Platinum, Palladium, peroxide, metal salts, Zinc,redox couples, enzymes, and combinations thereof.
 8. The solidifyingimplant composition of claim 1, further including suspended particles ofbiologically active material chosen from the group consisting ofantibiotics, therapeutic agents that stimulate bone healing, pain relieftherapeutics, cancer treatments, and combinations thereof.
 9. Thesolidifying implant composition of claim 1, further includingbiodegradable polymers chosen from the group consisting of polyglycolicacid (PGA), polylactic acid (PLA), polyglycolic-lactic acid (PGLA),polycaprolactone (PCL), ε-poly-L-lysine (EPA), glycosaminoglycans (GAGs,polyalcohols, heparinoids, and combinations thereof.
 10. The solidifyingimplant composition of claim 1, further including a material chosen fromthe group consisting of polymeric fibers, ceramic fibers, metal fibers,polymeric filaments, ceramic filaments, metal filaments, polymericcoils, ceramic coils, metal coils, polymeric particles, ceramicparticles, metal particles, and combinations thereof.
 11. Thesolidifying implant composition of claim 1, further including a liquidcontrast agent chosen from the group consisting of Ethiodol, Tantalum,Barium Sulfate, and Nickel-Titanium.
 12. The solidifying implantcomposition of claim 1, wherein said implant composition when solidifiedpossesses compressive strength within the range of 10-500 MPa, possesseselastic modulus between 0.1-100 GPa, and possesses yield strength within0.5-10 MPa.
 13. The solidifying implant composition of claim 1, whereinsaid implant composition when solidified includes pores in a size of1-1000 μm within said composition and less than 10 μum on a surface ofsaid composition.
 14. The solidifying implant composition of claim 1,wherein said composition is radiopaque and opacity of said compositiondiminishes over time.
 15. The solidifying implant composition of claim1, wherein said composition is chosen from the group consisting ofPLA-PGA co-polymer with a triol cross-linker in a DMSO solvent, PLA-PGAco-polymer with a triol cross-linker in a DMSO solvent with a polyHEMA(hydroxyethylmethacrylate) hydrogel, PLA-co-PGA and HEMA monomer in DMSOsolvent, PLA and PCL in DMSO with an AA (acrylic acid) monomer, PLA andPCL in DMSO with HEMA and AA monomers, PLA-co-PGA in DMSO with AAmonomer, PLA and PCL in DMSO with polyHEMA hydrogel and PEG, and PLA andPCL in DMSO with polyAA hydrogel and PEG.
 16. A method of treating apatient, including the steps of: implanting a solidifying implantcomposition comprising a polymeric material mixed with a biocompatiblesolvent into bone; and solidifying the implant composition.
 17. Themethod of claim 16, wherein said implanting step is further defined asinjecting the implant composition into the bone.
 18. The method of claim17, wherein said injecting step further includes the step of mixing theimplant composition before entry into the bone.
 19. The method of claim16, further including the step, prior to said implanting step, of mixingthe implant composition.
 20. The method of claim 18, wherein saidimplanting step is performed during a procedure chosen from the groupconsisting of vertebroplasty, kyphoplasty, void filling, bonestabilization, and stabilization of nonresorbable materials in contactwith bone.
 21. The method of claim 16, wherein said implanting step isfurther defined as treating a fracture is chosen from the groupconsisting of bone fractures, osteoporotic bone fractures, compressionfractures, stress fractures, pathological fractures, non-unionfractures, complex fractures, displaced fractures, and poor-healingfractures.
 22. The method of claim 16, wherein said solidifying step isfurther defined as solidifying the implant composition upon contact withsurrounding tissue or liquid by absorbing and diffusing the solvent intothe surrounding tissue or liquid.
 23. The method of claim 22, furtherincluding the step of forming pores within the implant composition andon the implant composition in place of the solvent.
 24. The method ofclaim 16, further including the step of allowing controlled movement ofbone with the implant composition.
 25. The method of claim 16, furtherincluding the step of absorbing and distributing stress and preventingfatigue and fracture of adjacent bone with the implant composition. 26.The method of claim 16, wherein the implant is chosen from the groupconsisting of permanent, biodegradable, and bioabsorbable.
 27. A methodof improving bone structure in patients, including the steps of:applying a solidifying implant composition comprising a polymericmaterial mixed with a biocompatible solvent to bone; shoring up bonestructure; and improving load bearing capacity and aiding healing ofmicrofractures.
 28. The method of claim 27, wherein said applying stepis further defined as a method chosen from the group consisting ofinjecting the implant composition into the bone, and coating thecomposition on the bone.
 29. The method of claim 27, wherein thepatients are suffering from a disease chosen from the group consistingof severe osteoporosis, metastases, and bone lesions at risk ofcatastrophic failure.
 30. The method of claim 27, further including thestep of temporarily stabilzing the implant composition after saidshoring up step.
 31. The method of claim 30, further including the stepof making subsequent procedures less difficult.
 32. The method of claim27, wherein the solidifying implant composition is chosen from the groupconsisting of permanent, biodegradable, and bioabsorbable.
 33. A methodof fixing an implant, including the steps of: applying a solidifyingimplant composition comprising a polymeric material mixed with abiocompatible solvent to an implant; and shoring up the implant.
 34. Themethod of claim 33, wherein the solidifying implant composition ischosen from the group consisting of permanent, biodegradable, andbioabsorbable.
 35. A method of devascularizing a tumor or vascularlesion, including the step of: applying a solidifying implantcomposition comprising a polymeric material mixed with a biocompatiblesolvent to a tumor or vascular lesion.
 36. The method of claim 35,further including the step of treating the tumor or vascular lesion witha therapeutic.
 37. A method of treating a vascular disease, includingthe step of: applying a solidifying implant composition comprising apolymeric material mixed with a biocompatible solvent to vascular sitein need of treatment.
 38. The method of claim 37, wherein the vasculardisease is chosen from the group consisting of an endoleak that occursfollowing endovascular repair of aortic aneurysms, aneurysms, spinal andbody arteriovenous malformations and fistulae, cerebral and spinal duralarteriovenous fistulae, traumatic vessel injury (traumatic vascularlesion), venous varices, visceral and/or viscerocutaneous fistulae,vascular tumors, and cerebral arteriovenous malformations.
 39. Themethod of claim 37, wherein said applying step is further defined asdelivering the composition into space that is filled by blood or bodyfluids, tracking the composition along the space, and filling in avascular site. radiopacity
 40. A method of treatinganeurysms/pseudoaneurysms, including the step of: applying a solidifyingimplant composition comprising a polymeric material mixed with abiocompatible solvent to an aneurysm/pseudoaneurysm.